Semaphorin 4A-expressing bone marrow-derived myeloid cells promote tumor progression

Background and aims Semaphorins (Semas) and Plexins are a family of proteins involved in the regulation of the tumor microenvironment and cancer growth. We previously described that Sema4A, overexpressed in myeloid cells under inflammatory conditions, exerted a pro-angiogenic effect. In this study, we investigated the role of Sema4A and its receptor in tumor-associated inflammation and cancer progression. Methods We silenced Sema4A in bone marrow-derived myeloid cells (BMCs), by means of lentiviral shRNA technology, in an orthotopic mouse model of pancreatic ductal adenocarcinoma (PDAC) and a transgenic mouse model of spontaneous multistep tumorigenesis of HPV16-induced cervical cancer (HPV16/E2). Results We observed increased levels of Sema4A and its receptors in PDAC and HPV16/E2 compared with normal tissues. Interestingly, we noticed that Sema4A was mainly expressed by myeloid cells and particularly by pro-tumoral M2-like macrophages. In addition, Sema4A was expressed in WT BMCs and up-regulated in PDAC or HPV16 BMCs. Hence, by silencing Sema4A in BMCs in tumor bearing mice we demonstrated that the lack of Sema4A expression significantly hampered tumor growth e metastasis spreading. Notably, we observed that Sema4A silencing induced a shift from M2 toward M1 anti-tumor phenotype, decreased regulatory T cells and normalized tumor vasculature in both PDAC and HPV16/E2 models. Finally, we observed that Sema4A promotes proliferation and migration of PDAC and that the depletion of PlexinB1 in these cells, reverted these effects. Conclusion We demonstrated that Sema4A expressed by BMCs contributes to tumor progression by acting on tumor-associated macrophages and T cells, and that its receptor PlexinB1 is mainly involved in Sema4A-induced tumor growth and invasiveness. In conclusion, Sema4A represents a novel biomarker for cancer progression and a new potential therapeutic target to inhibit the progression of pancreatic and cervical cancers.